Absence of phosphate retention? The precise sequence of metabolic anomalies in incipient CKD leading to secondary (2°) hyperparathyroidism remains a matter of debate. Many years ago, it was postulated that a retention of phosphate in the extracellular space due to the decrease in glomerular filtration rate and the accompanying reduction in plasma ionized calcium concentration was the primary event in the pathogenesis of 2° hyperparathyroidism. These anomalies would only be transient and a new steady state would rapidly occur, with normalized plasma calcium and phosphorus in response to excessive PTH secretion and the well-known effect of this hormone on tubular reabsorption of phosphate (“trade-off hypothesis” of Bricker and Slatopolsky) . However, this hypothesis has become less attractive since it was demonstrated that plasma phosphorus is not often elevated in early CKD. It is generally normal and may be even moderately diminished in some cases, and the urinary elimination of phosphate after an oral overload is actually accelerated . Nonetheless, one could argue that in early renal failure normal or even subnormal concentrations of plasma phosphorus might be observed subsequent to a slight, initial increase, causing an enhanced release of PTH which in turn corrects plasma phosphorus immediately, due to a permanent inhibition of tubular phosphate reabsorption. Another, recently identified factor involved in the control of serum phosphorus may also play a role, namely fibroblast growth factor-23 (FGF-23). It decreases plasma phosphorus by reducing tubular phosphate reabsorption similar to PTH, but decreases the renal synthesis of calcitriol, in contrast to the action of PTH. In turn, calcitriol and PTH appear to increase serum FGF-23 and calcitriol enhances FGF-23 production by the osteoblast . Dietary phosphate loading or deprivation in healthy volunteers did not lead to changes in FGF-23 serum levels in one study but did so in another . Moreover, it also induced changes in serum FGF-23 in normal mice and uremic rats Circulating FGF-23 levels increase with the progression of chronic renal failure, accentuates calcitriol deficiency, and thus probably contributes to the development of 2° hyperparathyroidism . It could even be predictive of refractory forms of parathyroid overfunction and of the response to calcitriol treatment.

Of note, a recent study identified slight increases of plasma phosphate in a large US population sample (NHANES III) with CKD stage 3, that is a creatinine clearance of 50-60 ml/min, as compared to a healthy control population without evidence of renal disease . It is possible that subtle changes in circulating and local factors involved in the control of phosphate balance determine the actual level of plasma phosphorus in CKD patients.

Calcium deficiency. In early CKD stages, disturbances of calcium metabolism may already be present. They include a calcium deficiency state due to a decrease in oral calcium intake and an impairment of active intestinal calcium absorption, a tendency towards hypocalcemia due to skeletal resistance to the action of PTH, and a reduced expression of the calcium-sensing receptor (CaR) in the parathyroid cell. All these factors may contribute to the development of parathyroid overfunction. Their relative importance increases with the progression of CKD. It also depends on individual patient characteristics such as the underlying type of nephropathy, comorbidities, dietary habits, and appetite.

Inhibition of calcitriol synthesis. A primary role of the disturbed renal synthesis of calcitriol in incipient CKD has become the preferred hypothesis in the last decade. A relative or absolute impairment of renal calcitriol production could well be the most important player in the initial sequence of events leading to secondary 2° hyperparathyroidism. The major underlying cause would be a reduced tubular transformation of 25OH vitamin D (calcidiol) to calcitriol, due to an intracellular accumulation of phosphate. In addition, the progressive loss of nephron mass and the well-known tendency towards metabolic acidosis could also play a role.

Another hypothesis can be proposed, based on the observation that calcidiol does not penetrate into proximal tubular epithelium from the basolateral side, but only from the luminal side. Thus it has been shown that the complex formed by calcidiol and its binding protein (DBP) has to be ultrafiltered by the glomerulus before it enters this epithelium from the apical side and serves as substrate for the renal enzyme, 1α-OH vitamin D hydroxylase . This obligate entry pathway was actually discovered in mice by serependicity, namely after the knock-out of the megalin gene, whose protein product is a multifunctional brush border membrane receptor. The deletion of this gene induced a state of vitamin D deficiency/rickets. It could then be shown that binding of the calcidiol/DBP complex to megalin was followed by endocytosis across the proximal tubule brush border membrane, thereby making the vitamin D metabolite available as a substrate for 1α-OH vitamin D hydroxylase and its transformation into calcitriol (Figure 1). In case of a reduction of glomerular filtration rate a decreased transfer of the calcidiol-DBP complex into the proximal tubular fluid would occur and hence a reduced availability of calcidiol substrate for luminal reabsorption and ultimately calcitriol formation. However, the validity for the human situation of this mechanism established in the mouse has subsequently been questioned since 1α-OH vitamin D hydroxylase expression was found not only in proximal, but also in distal tubular epithelium of human kidney, that is in tubular areas in which megalin apparently is not expressed . Further studies are needed to clarify whether a disturbance of tubular calcidiol reabsorption plays an important part in the 2° hyperparathyroidism of renal failure.

In addition, resistance to the stimulatory action of PTH on renal tubular 1α-OH vitamin D hydroxylase activity probably occurs as well. A disturbance of the calcitriol synthesis pathway could explain the long reported direct relation in CKD patients between plasma calcidiol and calcitriol, and between plasma calcitriol and glomerular filtration rate . Such relations are not observed in subjects with normal renal function.

Finally, the concentration of plasma calcidiol is often diminished due to insufficient hours of sunshine or sun exposure, intake of antiepileptic drugs, and enhanced urinary excretion of calcidiol complexed to DBP in the nephrotic syndrome or loss into the peritoneal cavity during CAPD treatment. All these factors may contribute to a reduction in calcitriol synthesis . However, low plasma calcidiol has also been postulated to be a risk factor per se for hyperparathyroidism, based on an observational study in Algerian hemodialysis patients with insufficient exposure to sunshine.